Process for the preparation of dihydropyridinecarboxylic acids

ABSTRACT

The invention relates to a process for the preparation of optically pure 1,4-dihydropyridinemonocarboxylic acids of the formula I ##STR1## in which the substituents have the meanings mentioned in the description.

This application is a 371 of PCT/EP91/02476 filed Dec. 20, 1991.

AREA OF APPLICATION OF THE INVENTION

The invention relates to a novel process for the preparation ofdihydropyridinecarboxylic acids. The compounds prepared according to theinvention are employed as precursors in the pharmaceutical industry.

KNOWN TECHNICAL BACKGROUND

Since the fact was made known that, in the area of calcium antagonistsof the 1,4-dihydropyridine type, in the case of chiral compounds oneenantiomer usually has a distinctly more strongly pronouncedcardiovascular action that the other, the need for a suitable,stereoselective synthesis or for a resolution into the enantiomers whichalso works on the industrial scale has continuously grown. This is seenin the multiplicity of publications and published patent applications,in which resolutions or enantioselective syntheses of chiral1,4-dihydropyridinecarboxylic acid derivatives are described.

In D. Enders et al. [Tetrahedron Letters 29, 6437 (1988)], anenantioselective synthesis of 1,4-dihydropyridine is described in whichthe intermediate condensation with a chiral hydrazine leads to a productwhich is greatly enriched (84 to 98% purity) in one enantiomer. B. Lammand R. Simonsson [Tetrahedron Letters 30, 6423 (1989)] describe theresolution of felodipine into the enantiomers with the aid of anoptically active alcohol. In attempts to obtain manidipine [Drugs of thefuture 15, 311 (1990)] or alternatively other pharmacologicallyinteresting 1,4-dihydropyridines [such as, e.g., YM-09730, J. Med. Chem.29, 2504 (1986)] in optically pure form, the synthesis has usually stillbeen carried out recently by the method described in Shibanuma et al.[Chem. Pharm. Bull. 28, 2809 (1980)], in which the monocarboxylic acidregarded as the key compound is prepared from the diester by hydrolysisusing sodium 1-dimethylamino-2-propanolate and 2% water. Novel routes tocorresponding monocarboxylic acids are described in International PatentApplications WO88/07524 and WO88/09931.

DESCRIPTION OF THE INVENTION

Surprisingly, a route which is particularly problem-free and can easilybe used on the industrial scale for the preparation and processing ofthe 1,4-dihydropyridinemonocarboxylic acids described in Shibanuma etal. (see above) and regarded as key intermediates has now been found.The invention thus relates to a process for the preparation of opticallypure 1,4-dihydropyridinemonocarboxylic acids of the formula I ##STR2##in which R1 denotes 1-4C-alkyl,

R2 denotes 1-4C-alkyl,

R3 denotes 1-4C-alkyl or benzyl, and either

A denotes hydrogen and

B denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl,2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl),2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or2-difluoromethoxyphenyl radical, or

A denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl,2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl),2-trifluorobenzoimidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl,2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical and

B denotes hydrogen.

The process in a first aspect comprises hydrolysing a compound of theformula II ##STR3## in which R1, R2, R3, A and B have the abovementionedmeanings, in an alcohol R1--OH using aqueous alkali metal hydroxide andresolving the resultant acid III ##STR4## into the enantiomers in thecustomary manner. In a further aspect, the process comprises employingthe undesired enantiomer, after ester formation with the compound R1--Xin which R1 has the abovementioned meaning and X represents a leavinggroup or a halocarbonyloxy group, again as the starting compound II.

1-4C-alkyl represents methyl, ethyl, propyl, butyl, isopropyl, isobutyl,sec-butyl and tert-butyl. Preferred 1-4C-alkyl radicals R1 are isobutyl,isopropyl and in particular ethyl and methyl. Preferred 1-4C-alkylradicals R2 are ethyl and methyl. A preferred 1-4C-alkyl radical R3 isethyl.

The hydrolysis in the alcohol R1--OH is advantageously carried out at adilution ratio (compound II:alcohol) of 1:3 to 1:40, preferably 1:5 to1:10.

A suitable aqueous alkali metal hydroxide is in particular 0.3- or10-molar, preferably 0.5- to 2-molar, sodium hydroxide solution orpotassium hydroxide solution, where--relative to the compound II--0.9 to1.5 equivalents, preferably 0.95 to 1.20 equivalents, in particular 1.0equivalent, of alkali metal hydroxide is employed.

The hydrolysis is preferably carried out at temperatures between 50° and120° C., in particular at the boiling point of the alcohol R1--OH used.

The acid III formed by the hydrolysis, which is present as a racemate,can be resolved into the enantiomers in a customary manner via thediastereomeric salts using enantiomerically pure, optically active bases[see, e.g., Chem. Parm. Bull. 28, 2809 (1980)].

The undesired or unrequired optically pure acid III is esterified withthe compound R1--X in a manner familiar per se to the person skilled inthe art. The leaving group X of the compound R1--X is a group which iseasily removed during the ester formation, for example a halogen atom,such as chlorine, bromine or iodine, or preferably the alkylsulfategroup. X is just as preferably a halocarbonyloxy group, in particularthe chlorocarbonyloxy group, such that the compound R1--X is an alkylchloroformate.

The reaction of the compound III with the compound R1--X is preferablycarried out under basic conditions, preferably in the presence of aphase transfer catalyst. Catalysts which may be mentioned in addition toonium salts, such as e.g., tetrabutylammonium bromide orbenzyltriethylammonium chloride, are especially crown ethers, such asdibenzo-[18]crown-6, dicyclohexyl[18]crown-6 and in particular[18]crown-6.

Possible bases, which are employed at least in a molar ratio, preferablyin excess, are inorganic bases, such as alkali metal hydroxides (e.g.sodium hydroxide or potassium hydroxide), or in particular alkali metalcarbonates, (e.g. sodium carbonate or preferably potassium carbonate).When working in an anhydrous solvent, the hydroxides or carbonates usedare preferably employed in finely powdered form.

The reaction is carried out (depending on the type of phase transfercatalyst and the base employed) in water-containing or anhydrous organicsolvents, or in a mixture of water and an organic solvent which isimmiscible or hardly miscible with water. Water/solvent mixtures whichmay be mentioned are, for example, the mixtures of water withchloroform, dichloromethane or toluene. Water-containing or anhydroussolvents which may be mentioned are, for example, dichloromethane,acetonitrile or in particular acetone, methyl ethyl ketone or methylisobutyl ketone.

The reaction is carried out (depending on the type of compound R1--Xemployed) at temperature between 20° and 150° C., where, for example, inthe reaction with dimethyl sulfate temperatures between 20° and 60° C.and in the reaction with methyl chloroformate temperatures between 50°and 120° C. are preferred.

An embodiment of the invention (embodiment a) relates to a process forthe preparation of optically pure 1,4-dihydropyridinecarboxylic acids ofthe formula Ia ##STR5## in which R1 denotes 1-4C-alkyl,

R2 denotes 1-4C-alkyl,

R3 denotes 1-4C-alkyl or benzyl and

Ar denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl,2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl),2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or2-difluoromethoxyphenyl radical.

The process comprises hydrolysing a racemate of the formula IV ##STR6##in which R1, R2, R3 and Ar have the abovementioned meanings, in analcohol R1--OH using aqueous alkali metal hydroxide, resolving theresultant racemic acid V ##STR7## in a customary manner into theenantiomers Ia and Ib ##STR8## and employing the enantiomer Ib, afterester formation with the compound R1--X in which R1 has theabovementioned meaning and X represents a suitable leaving group or ahalocarbonyloxy group, again as the starting compound IV.

A further embodiment of the invention (embodiment b) relates to aprocess for the preparation of optically pure1,4-dihydropyridinecarboxylic acids of the formula Ib ##STR9## in whichR1 denotes 1-4C-alkyl,

R2 denotes 1-4C-alkyl,

R3 denotes 1-4C-alkyl or benzyl and

Ar denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl,2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl),2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or2-difluoromethoxyphenyl radical.

The process comprises hydrolysing a racemate of the formula IV ##STR10##in which R1, R2, R3 and Ar have the abovementioned meanings, in analcohol R1--OH using aqueous alkali metal hydroxide, resolving theresultant racemic acid V ##STR11## in a customary manner into theenantiomers Ia and Ib ##STR12## and employing the enantiomer Ia, afterester formation with the compound R1--X in which R1 has theabovementioned meaning and X represents a suitable leaving group or ahalocarbonyloxy group, again as the starting compound IV.

Preferred compounds prepared by the processes of embodiments a and b arethose of the formulae Ia and Ib, in which

R1 denotes 1-4C-alkyl,

R2 denotes 1-4C-alkyl,

R3 denotes 1-4C-alkyl, and

Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl.

Particularly preferred compounds prepared by the processes ofembodiments a and b are those of the formulae Ia and Ib, in which

R1 denotes methyl or ethyl,

R2 denotes methyl,

R3 denotes ethyl and

Ar denotes 3-nitrophenyl.

The following examples illustrate the invention in greater detail. M.p.represents melting point, h represents hour(s) and min representsminute(s).

EXAMPLES 1.(±)-1-Ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid

a) 50 g (0.124 mol) of dimethyl(±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylateare heated to boiling under reflux for 24 h in 500 ml of methanol afteraddition of 136 ml of 1N potassium hydroxide solution. After distillingoff 350 ml of methanol, 300 ml of water are added. The mixture isclarified with the addition of 5 g of active carbon, 2N hydrochloricacid is added dropwise to the filtrate to pH 3, and the precipitatedsolid is filtered off, washed with water until chloride-free and driedto constant weight (40° C./vacuum. 44 g (91% of theory) of the titlecompound of m.p. 182°-183° C. are obtained.

b) The title compound is also obtained if in procedure 1a) the 1Npotassium hydroxide solution is replaced by the same amount of 1N sodiumhydroxide solution. Yield: 40 g (83% of theory) of beige powder. Afterstirring in 300 ml of hot methanol, 34.4 g (71%) of the title compoundof m.p. 184°-185° C. are obtained.

c) The title compound is also obtained if in procedure 1a) the 1.1equivalents of 1N potassium hydroxide solution are replaced by 1.3equivalents of 4N potassium hydroxide solution. Starting from 5.15 g ofdimethyl ester, in this case 4.0 g (83% of theory) of the title compoundof m.p. 177°-178° C. are obtained.

2. (±)-1-Ethoxymethyl-1,4-dihydro-5-ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid

By the procedure described in Example 1a), 1.4 g (75% of theory) of thetitle compound m.p. 188°-189° C. are obtained as a beige crystal powderfrom 2 g of diethyl (±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate in 20 ml of ethanol using 5.1 ml(1 mmol) of 1N potassium hydroxide solution (1.1 equivalents) after 40 hunder reflux and with identical working up.

3. (±)-4-(2,3-Dichlorophenyl-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylic acid

By the procedure described in Example 1a), 1.4 g (72% of theory) of thetitle compound of m.p. 168°-169° C. are obtained from 2 g (4.7 mmol) ofdimethyl(±)-4-(2,3-dichlorophenyl)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylatein 20 ml of methanol containing 5.2 ml of 1N potassium hydroxidesolution after 60 h under reflux and with identical working up.

4. Dimethyl(±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

a) 280 g (0.717 mol) of the acid which is no longer required after theresolution of the racemate are suspended in 3 l of acetone; 300 g ofpowdered potassium carbonate and 1 g of [18]crown-6 are added and 71.5ml (0.75 mol) of dimethyl sulfate are added dropwise at 25° C. withstirring in the course of 1 hour. After a stirring time of 5 h (internaltemperature 25°-30° C.), 30 ml of triethylamine are added to removeexcess dimethyl sulfate and the mixture is allowed to react tocompletion for 18 h. It is then filtered, the filtrate is concentratedin vacuo in a rotary evaporator and the residue is crystallized byaddition of diisopropyl ether. 244 g (84% of theory) of dimethyl(±)-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylateare obtained in the form of beige crystals of m.p. 86°-88° C.

b) The title compound is also obtained by the following process: 30 g(77 mmol) of the acid which is no longer required after the resolutionof the racemate are heated at reflux temperature for 2 hours togetherwith potassium carbonate (31 g, 231 mmol), methyl chloroformate (7.6 g,85 mmol) and [18]crown-6 (0.3 g) in 400 ml of isobutyl methyl ketone.After cooling to 20° C., inorganic salts are filtered off and thefiltrate is completely concentrated. The oily residue is crystallizedfrom methanol/water. The title compound (25 g; 80% of theory) isobtained in the form of a beige crystal powder; m.p. 85°-87° C.

TECHNICAL APPLICABILITY

A process is made available by means of the invention by whichenantiomerically pure 5-alkoxycarbonyl-1,4-dihydropyridine-3-carboxylicacids, which are required as useful intermediates for the synthesis ofenantiomerically pure, pharmacologically active1,4-dihydropyridine-3,5-dicarboxylic acid diesters, can be prepared by asimple route and in high yield.

In Sausin et al. (Khimiya Geterotsiklicheskikh Soedinenii, No. 2, p.272, February 1978) the partial hydrolysis of N-alkylated dialkyl1,4-dihydropyridinedicarboxylates using potassium hydroxide solution isadmittedly described, and in European Patent Application 202,652 thepartial hydrolysis of N-unsubstituted dialkyl1,4-dihydropyridinedicarboxylates is reported. These publications,however, have not suggested to the person skilled in the art to attemptthe partial hydrolysis of a dialkyl 1,4-dihydropyridinedicarboxylate,which carries on the nitrogen a protective group which is easilyremovable in principle (such as, e.g., in this case --CH₂ --OR₃). Hadthe partial hydrolysis according to the invention actually beensuggested, then it would have been employed a long time ago in theheavily researched area of the 1,4-dihydropyridines. However, this isnot the case. The recent publications, in which the synthesis ofenantiomerically pure 1,4-dihydropyridinemonocarboxylic acids asintermediates is described, refer rather to the substantially moreinvolved and complicated synthesis according to Shibanuma et al. (seeabove). The process according to the invention thus does not follow inan obvious manner from the prior art for the person skilled in the art.

In addition to the hydrolysis of the diester to the monoester, whichproceeds in high yields and is completely straightforward, the recyclingof the unrequired chiral monoester to the non-chiral diester is afurther important aspect of the process. As a result of the"racemization" of the unrequired compound (which otherwise would have tobe disposed of) and its reintroduction into the preparation cycle, thepreparation costs for the desired final product are distinctly reduced.

The processing of the intermediates prepared by the process according tothe invention to give pharmacologically active final products isdescribed, for example, in International Patent Applications WO88/07524and WO88/07525.

I claim:
 1. A process for the preparation of an optically pure 1,4-dihydropyridinemonomcarboxylic acid of formula I ##STR13## in which R1 denotes 1-4C-alkyl,R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl or benzyl, and either A denotes hydrogen and B denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical, or A denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical and B denotes hydrogen,which comprises hydrolysing a compound of the formula II ##STR14## in which R1, R2, R3, A and B have the abovementioned meanings, in an alcohol R1--OH using aqueous alkali metal hydroxide, resolving the resultant acid III ##STR15## into the enantiomers in a customary manner and employing the undesired enantiomer, after ester formation with the compound R1--X having the abovementioned meaning throughout this claim and X representing a leaving group or a halocarbonyloxy group, again as the starting compound II.
 2. The process as claimed in claim 1, for the preparation of an optically pure 1,4-dihydropyridinecarboxylic acid of the formula Ia ##STR16## in which R1 denotes 1-4C-alkyl,R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl or benzyl and Ar denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical,which comprises hydrolysing a racemate of the formula IV ##STR17## in which R1, R2, R3 and Ar have the abovementioned meanings, in an alcohol R1--OH using aqueous alkali metal hydroxide, resolving the resultant racemic acid V ##STR18## in a customary manner into the enantiomers Ia and Ib ##STR19## and employing the enantiomer Ib, after ester formation with the compound R1--X, in having the abovementioned meaning throughout this claim and X representing a suitable leaving group or a halocarbonyloxy group, again as the starting compound IV.
 3. The process as claimed in claim 1 for the preparation of an optically pure 1,4-dihydropyridinecarboxylic acid of the formula Ib ##STR20## in which R1 denotes 1-4C-alkyl,R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl or benzyl and Ar denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical,which comprises hydrolysing a racemate of the formula IV ##STR21## in which R1, R2, R3 and Ar have the abovementioned meanings, in an alcohol R1--OH using aqueous alkali metal hydroxide, resolving the resultant racemic acid V ##STR22## in a customary manner into the enantiomers Ia and Ib ##STR23## and employing the enantiomer Ia, after ester formation with the compound R1--X, R1 having the abovementioned meaning throughout this claim and X representing a suitable leaving group or a halocarbonyloxy group, again as the starting compound IV.
 4. The process as claimed in claim 2, wherein a compound of the formula Ia is prepared in whichR1 denotes 1-4C-alkyl, R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl, and Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl.
 5. The process as claimed in claim 3, wherein a compound of the formula Ib is prepared in whichR1 denotes 1-4C-alkyl, R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl, and Ar denotes 3-nitrophenyl or 2,3-dichlorophenyl.
 6. The process as claimed in claim 2, wherein a compound of the formula Ia is prepared in whichR1 denotes methyl or ethyl, R2 denotes methyl, R3 denotes ethyl and Ar denotes 3-nitrophenyl.
 7. The process as claimed in claim 3, wherein a compound of the formula Ib is prepared in whichR1 denotes methyl or ethyl, R2 denotes methyl, R3 denotes ethyl and Ar denotes 3-nitrophenyl.
 8. A process for the preparation of an optically pure 1,4-dihydropyridinemonocarboxylic acid of formula I ##STR24## in which R1 denotes 1-4C-alkyl,R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl or benzyl, and either A denotes hydrogen and B denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical, or A denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical and B denotes hydrogen,which comprises hydrolysing a compound of the formula II ##STR25## in which R1, R2, R3, A and B have the abovementioned meanings, in an alcohol R1--OH R1 being 1-4C-alkyl using aqueous alkali metal hydroxide, and resolving the resultant acid III ##STR26## into the enantiomers in a customary manner.
 9. A process for the preparation of an optically pure 1,4-dihydropyridinemonocarboxylic acid of the formula I ##STR27## in which R1 denotes 1-4C-alkyl,R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl or benzyl, and either A denotes hydrogen and B denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical, or A denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical and B denotes hydrogen,by partial hydrolysis of a compound of the formula II ##STR28## in which R1, R2, R3, A and B have the abovementioned meanings, to give an acid III ##STR29## and resolution into the enantiomers in a customary manner, which comprises employing the undesired enantiomer, after ester formation with the compound R1--X in which R1 has the abovementioned meaning and X represents a leaving group or a halocarbonyloxy group, again as the starting compound II.
 10. A process for the preparation of an 1,4-dihydropyridinemonocarboxylic acid of the formula III ##STR30## in which R1 denotes 1-4C-alkyl,R2 denotes 1-4C-alkyl, R3 denotes 1-4C-alkyl or benzyl, and A denotes hydrogen and B denotes a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical,which comprises hydrolysing a compound of the formula II ##STR31## in which R1, R2, R3, A and B have the abovementioned meanings, in an alcohol R1--OH R1 being 1-4C-alkyl using aqueous alkali metal hydroxide. 